Cytotoxic marine natural products

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

The first total synthesis of the potent cytotoxic marine natural product makaluvamine F (5) involved the preparation of 2,3-dihydrobenzothiophene 2 <99CC143>. Debenzylation and subsequent acid-catalyzed cyclization of thioether 1 gave 2 which was converted in four steps to 2-azido-2,3-dihydrobenzothiophene 3 using a combination of Phl=0 and McjSiNj for installation of the azide. Reduction of the azide followed by coupling the resultant amine with pyrroloiminoquinone 4 then gave makaluvamine F (5). 

The formation of a highly complex 2,5-disubstituted dihydropyran by RCM was one of the key steps in Snapper s total synthesis of the cytotoxic marine natural product (-l-)-cacospongionolide B 111 (Scheme 19). With catalyst C, RCM of triene 108 proceeded regioselectively to produce only the dihydropyran... 

In the laboratory of F.R. Kinder Jr., the total synthesis of cytotoxic marine natural product bengamide E was... 

W. Fenical P. R. Jensen X. C. Cheng, Halimide, a Cytotoxic Marine Natural Product, and Derivatives Thereof. U.S. Patent 6,069,146, 1998. 

Fenical W, Jensen PR, Cheng XC (2000) Avrainvillamide, a cytotoxic marine natural product, and derivatives thereof. U.S. Patent 6,066,635... 

Another very popular and efficient method to synthesize pyridazines remains the inverse electron demand Diels-Alder reactions of 1,2,4,5-tctrazines with electron rich dienophiles. Wan and Snyder reported the (4 + 2]-cycloaddition of the readily available tetrazine 121 with A-protected 2-aminoimidazole 120 to obtain pyridazine 122 (86%). Subsequent deprotection and decarboxylation gave 123, the structure originally assigned to zarzissine, a cytotoxic marine natural product <01T5497>. Zarzissine was then reassigned as the imidazole(4,5-bjpyrazine 124. 

M. Bayet-Robert, S. Lim, C. Barthomeuf, and D. Morvan, Biochemical disorders induced by cytotoxic marine natural products in breast cancer cells as revealed by proton NMR spectroscopy -based metabolomics. Biochem. Pharmacol, 80 (2010) 1170-9. 

Later on, Christmann, et al. developed an organocatalytic intramolecular Diels-Alder reaction of a,P-unsaturated dialdehydes, providing the bicyclic systems (such as decalins 13), [8] (Scheme 3.3). The mechanism was assumed to undergo the vinylogous enamine activation [9], followed by a rapid IMDA reaction and subsequent 6-hydride elimination. On the other hand, the synthesis of the cytotoxic marine natural product amaminol B (16) was achieved by Christmann and his co-workers with the key step of the organocatalytic IMDA reaction of 14, Scheme 3.4 [10]. 

Whereas the initial aldol stereoselectivity was very low, eventually resulting in the final epimeric mixture of products, the stereoselectivity of the Prins cydization was remarkably high, furnishing the 2,6-ds configuration exdusivdy. This methodology was successfully employed in a stereoselective synthesis of the cytotoxic marine natural product leucascandrohde A by the Rychnovsky group. 

In the enantioselective synthesis of the C-l-C-28 portion of cytotoxic marine natural product amphidinolide B1217, Lee [47] developed a strategy using the key steps of the Evans oxazohdinone alkylation, Sharpless epoxidation and orthoester Claisen rearrangement AUylic alcohol 218 as a mixture of diastereomers gave rise after treatment with triethyl orthoacetate under acidic catalysis to ester 219 in 66% yield (Scheme 6.34). This result exemplifies the potency of the orthoester rearrangement even with such probably sensitive epoxyallylic alcohol. 

As part of their investigations towards the synthesis of the cytotoxic marine natural product diazonamide A, Feldman et al. discovered a noteworthy atroposelective macrolactonisation reaction. Thus, the ring closure of the configurationally flexible model bisindole depicted in Scheme 5.29 afforded the corresponding lactone as a single isomer. The bulk of the NB0C2 group was... 

Shair and co-workers turned their attention to the regiochemical outcome of enyne-metathesis macrocyclizations, and they completed the biomimetic synthesis of a cytotoxic marine natural product (—)-longithorone A (204, Scheme 24.51). Biosynthetically, the natural product has been proposed originating from two [12]-paracyclophanes 205 and 206 by two Diels-Alder reactions, and thus, the authors applied enyne metathesis macrocyclization to the preparations of paracyclophanes 205 and 206. Both metathesis precmsors 208 and 210 were prepared from the common intermediate 207. The cyclization of enyne 208 in the presence of [Ru]-Ia (50mol%) in refluxing CH2CI2 under ethylene atmosphere proceeded with excellent atropdiastereoselectivity and -stereoselectivity. On the other hand, the macrocyclization of enyne 210 was less atropdiastereoselective (selective formation of the endocy-clic olefin ( /Z= 3.9 1). Nevertheless, the desired product 211 was obtained in 31% yield. In the absence of ethylene, neither macrocyclization of 208 nor 210 occurred. 

Usami, Y, Suzuki, K., Mizuki, K., Ichikawa, H., and Arimoto, M. (2009a) Synthesis of (—)-pericosine B, the antipode of the cytotoxic marine natural product. Org. Biomol. Chem., 7, 315-318. 

Heathcock, C.H. and Smith, S.C. (1994) Synthesis and biological activity of unsymmetrical bis-steroidal pyrazines related to the cytotoxic marine natural product cephalostatin 1. J. Org. Chem., 59, 6828-6839. Erratum J. Org. Chem., 60, 6641 (1995). 

The macrocydic core of diazonamide A, a cytotoxic marine natural product has been prepared by Vedejs via Suzuki coupling of boronic acid 73 and the triflate 74 yielding interconverting mixture of two atropisomers that on treatment with LDA at -23 °C affords the macrocydic ketone 75 in 57% yield (Scheme 3.33) [52]. 

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